1. Field of the Invention
The present invention is directed to novel 4'-deshydroxyepipodophyllotoxin glucosides, to methods of preparing these new compounds, and to the therapeutic use of the compounds in inhibiting the growth of mammalian tumors.
2. Description of the Prior Art
Etoposide (VP-16, Ia) and teniposide (VM-26, Ib) are clinically useful anticancer drugs derived from the naturally occurring lignan, podophyllotoxin (II). The numbering system used for nomenclature purposes is shown in Formula II. Etoposide and teniposide are epipodophyllotoxin derivatives; epipodophyllotoxin being the epimer of podophyllotoxin at the 4-position. Etoposide and teniposide are active in the treatment of a variety of cancers including small cell lung cancer, non-lymphocytic leukemia and non-seminomatous testicular cancer. ##STR1##
Etoposide and teniposide and methods for their preparation are disclosed in U.S. Pat. No. 3,524,844 and J. Med. Chem. 14 (10): 936-940, 1971. Encompassed by the above-mentioned references are compounds of formula I above in which R.sup.2 is hydrogen and R.sup.1 is selected from the group consisting of C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.3 -C.sub.7 cycloalkyl, furyl, thienyl, pyridyl, pyrrolyl, C.sub.6 -C.sub.10 aryl and C.sub.7 -C.sub.14 aralkyl, said aryl and aralkyl rings optionally bearing one or more substituents selected from halo, C.sub.1 -C.sub.4 alkyl, nitro, hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkanoyloxy, cyano, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4)alkylamino, carboxy, C.sub.1 -C.sub.4 alkylthio, mercapto, C.sub.2 -C.sub.4 alkenoylamino, C.sub.1 -C.sub.4 alkanoyl, C.sub.2 -C.sub.4 alkenyl and carbamoyl; or R.sup.1 and R.sup.2 are each C.sub.1 - C.sub.10 alkyl; or R.sup.1 and R.sup.2 and the carbon atom to which they are attached join to form a C.sub.5 -C.sub.6 cycloalkyl group.
The etoposide 3',4'-orthoquinone IIIa shown below is derived from the oxidation of etoposide as described in U.S. Pat. No. 4,609,644. This quinone IIIa has been implicated as a reactive intermediate in the metabolic activation of etoposide by rat liver and hela microsomal fractions (Proc. Am. Assoc. Cancer Res. 24, 319, 1983) and also has been suggested as a bioalkylating agent in a report describing the metabolism of etoposide by mouse liver microsomes (see Haim, N; Nemec, J.; Roman, J.; Sinha, B. K. presented at the American Society for Pharmacology and Experimental Therapeutics meetings at Boston, MA, Aug. 18-22, 1985). In addition the peroxidative activation of etoposide or teniposide has been shown to result in the formation of two metabolites, one of which has been identified as the corresponding orthoquinone III (see Haim, N.; Roman, J.; Nemec, J.; Sinha, B. K. Biochemical and Biophysical Research Communications 135, 215, 1986). These same authors have shown that the peroxidative activation of these drugs produces phenoxy radical intermediates and propose that concomitant O-demethylation to the orthoquinone of formula III may be important in the mechanism of action of etoposide and teniposide. Etoposide 3',4'-orthoquinone IIIa has been generated, isolated and characterized from the electrochemical oxidation of etoposide (see J. Electroanal. Chem. 184: 317, 1985). ##STR2##
The 4'-deshydroxyetoposide analog IVa would be incapable of producing the 3',4'-ortho-quinone IIIa, and thus any biological activity attributed to it would most likely be due to an alternative mechanism of action such as inhibition of DNA topoisomerase II. Moreover, since a free hydroxyl group at the 4'-position of etoposide and teniposide has been regarded as essential for DNA breakage activity (see Biochemistry 23: 1183, 1984), the corresponding 4'-deshydroxy analog would not be expected to cause DNA strand cleavage and thus should show little or no antitumor activity in-vitro and in-vivo. ##STR3##
Surprisingly, we have prepared the 4'-deshydroxy compounds of formula IV and have shown them to have significant antitumor activity both in-vitro and in-vivo against various tumor systems.